The negative impact of T cell-mediated rejection on renal allograft survival in the modern era

Abstract

The prevalence and long-term impact of T cell-mediated rejection (TCMR) is poorly defined in the modern era of tacrolimus/mycophenolate-based maintenance therapy. This observational study evaluated 775 kidney transplant recipients with serial histology and correlated TCMR events with the risk of graft loss. After a ~30% incidence of a first Banff Borderline or greater TCMR detected on for-cause (17%) or surveillance (13%) biopsies, persistent (37.4%) or subsequent (26.3%) TCMR occurred in 64% of recipients on follow-up biopsies. Alloimmune risk categories based on the HLA-DR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events (p = .002) and Banff TCMR grade (p = .007). Both a first and second TCMR event correlated with death-censored and all-cause graft loss when adjusted for baseline covariates and other significant time-dependent covariates such as DGF and ABMR. Therefore, a substantial portion of kidney transplant recipients, especially those with intermediate and high HLA-DR/DQ molecular mismatch scores, remain under-immunosuppressed, which in turn identifies the need for novel agents that can more effectively prevent or treat TCMR.

Keywords: T cell-mediated rejection; antibody-mediated rejection; clinical research/practice; graft survival; histocompatibility; immunosuppression/immune modulation; kidney transplantation; patient survival.

FIGURE 1

Timing of biopsies and rejection prevalence. For‐cause (A) and surveillance (B) biopsies shown up to month 60 categorized by adult (orange circles) or pediatric (black circles). After 60 months 182 further biopsies were performed (range 61–220 months) including n = 28 surveillance and n = 154 for‐cause biopsies. Biopsy proven rejection prevalence in the month 0–60 shown in (C)

FIGURE 2

Patient flow diagram

FIGURE 3

First T cell–mediated rejection Banff grade. Percentage of Banff grades of first T cell–mediated rejection (TCMR) events (n = 229) split by surveillance (green bars) or for‐cause (gray bars)

FIGURE 4

The number of recipients by the number of TCMR episodes. Following a first T cell–mediated rejection (TCMR) event, successive follow‐up biopsies revealed that a persistent or subsequent TCMR events occurred in ≥50% of recipients at a later timepoint. Banff borderline TCMR was the most common TCMR phenotype

FIGURE 5

T cell–mediated rejection episodes by HLA‐DR/DQ molecular mismatch category. HLA‐DR/DQ single molecule eplet mismatch results were used to categorize patients into low, intermediate, or molecular mismatch categories using previously published thresholds (Wiebe et al.). Chi‐squared test revealed an association between HLA‐DR/DQ molecular mismatch categories and the number of TCMR episodes (p = .002)

FIGURE 6

Most severe T cell–mediated Banff grade by HLA‐DR/DQ molecular mismatch category. HLA‐DR/DQ single molecule eplet mismatch results were used to categorize patients into low, intermediate, or high molecular mismatch categories using previously published thresholds (Wiebe et al. ¹⁶ ). Chi‐squared test revealed an association between HLA‐DR/DQ molecular mismatch categories and the most severe Banff TCMR diagnosis (p = .007)